Crystalline Minocycline Base and Processes for its Preparation

ABSTRACT

The invention provides crystalline minocycline base. In particular, three crystalline polymorphic forms, designated Form I, Form II and Form III, of minocycline base are provided. These are characterised by XRD and IR data. Processes for preparing the new polymorphic forms are also provided. For example, Form I is prepared by dissolving and/or suspending amorphous minocycline base in an organic solvent chosen from ethers followed by crystallisation from the mixture.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 12/528,209filed, Nov. 4, 2009, now U.S. Pat. No. 8,258,327 issued Sep. 4, 2012,which is a national stage application filed under 35 USC §371 ofinternational application PCT/GB08/00625 file Feb. 22, 2008, whichclaims the priority to PT 103661 filed Feb. 23, 2007, the entiredisclosures of which are expressly incorporated herein by reference

DESCRIPTION

The present invention provides crystalline minocycline base includingthree new polymorphic forms thereof, and also describes a process toobtain pure minocycline base in a crystalline form wherein all theimpurities are controlled, especially the impurity 4-epi minocycline, tovery low levels.

BACKGROUND OF THE INVENTION

Minocycline is a member of the broad spectrum tetracycline antibiotics,which has a broader spectrum than the other members of this group ofcompounds.

Minocycline is widely used in therapy, primarily to treat acne androsacea at a once daily dose of 100 mg.

The preparation of minocycline is disclosed in U.S. Pat. No. 3,148,212;U.S. Pat. No. 3,226,436 and U.S. Pat. No. 4,849,136.

Minocycline may be used as base per se or as non-toxic acid additionsalts of organic or inorganic acids, e.g., sulfonic, trichloroacetic orhydrochloric acid.

Minocycline base, previously known before this invention only in theamorphous form, is not as stable as the corresponding acid additionsalts and hence, methods to provide a stable form of minocycline basewhich makes its use promising as an active ingredient have beenexamined.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: X-ray diffraction pattern of crystalline Form I of minocyclinebase.

FIG. 2: Infrared spectrum of crystalline Form I of minocycline base.

FIG. 3: X-ray diffraction pattern of crystalline Form II of minocyclinebase.

FIG. 4: Infrared spectrum of crystalline Form II of minocycline base.

FIG. 5: X-ray diffraction pattern of crystalline Form III of minocyclinebase.

FIG. 6: Infrared spectrum of crystalline Form III of minocycline base.

FIG. 7: X-ray diffraction pattern of amorphous minocycline base.

FIG. 8: Infrared spectrum of amorphous minocycline base.

DETAILED DESCRIPTION

The present invention describes crystalline minocycline base, includingnew polymorphic forms of crystalline minocycline base and novelprocesses for their preparation.

The present inventors have now found that, surprisingly, minocyclinebase can in fact be provided in a stable crystalline form. They havealso found three new polymorphic forms of crystalline minocycline base.

Accordingly, in its broadest aspect, the invention provides crystallineminocycline base.

In one aspect, polymorphic Form I of crystalline minocycline base isprovided. That this is a crystalline form of minocycline base, which upuntil now has only been known in its amorphous form, is demonstrated byphysical attributes whose application in this area is well known tothose skilled in the art.

Crystalline Form I of minocycline base has a characteristic X-raydiffraction pattern shown in FIG. 1 and an infrared spectrum of FIG. 2.

Crystalline Form 1 is characterised by an X-ray diffraction patternhaving peaks at 5.2, 7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8,19.3, 19.5, 20.7, 21.3, 21.8, 22.3, 23.1, 24.0, 25.3, 25.7 and26.5.+−.0.2°2.theta., as given in FIG. 1. It is further characterised byan infrared spectrum having peaks at 1646, 1602, 1581, 1470, 1397, 1364,1286, 1218, 1182, 1134, 1072, 1061, 1023, 1001, 969, 950, 874, 850, 716,636, 620 and 545.+−.4 cm.⁻¹ as given in FIG. 2.

In another aspect, the invention provides a process for the preparationof polymorphic Form I of crystalline minocycline base, which processcomprises dissolving and/or suspending amorphous minocycline base in anorganic solvent chosen from ethers followed by crystallization from themixture.

Preferably, the process comprises suspending amorphous minocycline basein an organic solvent chosen from ethers, cooling the heterogeneousmixture to a temperature of from 0° C. to 30° C., the preferred rangebeing from 10° C. to 15° C. and isolating Form I from the reactionmixture.

Any suitable ether solvent may be used, but is preferred to use methyltert-butyl ether.

In another aspect, polymorphic Form II of crystalline minocycline baseis provided. That this is a crystalline form of minocycline base, whichup until now has only been known in its amorphous form, is demonstratedby physical attributes whose application in this area is well known tothose skilled in the art.

Crystalline Form II of minocycline base has a characteristic X-raydiffraction pattern shown in FIG. 3 and an infrared spectrum of FIG. 4.

Crystalline Form II is characterised by an X-ray diffraction patternhaving peaks at 3.4, 6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1,17.6, 17.8, 18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3,27.1, 27.5, 28.0 and 29.1.+−.0.2°2.theta., as given in FIG. 3. It isfurther characterised by an infrared spectrum having peaks at 1644,1607, 1582, 1469, 1453, 1413, 1396, 1358, 1287, 1251, 1217, 1186, 1166,1136, 1061, 999, 970, 874, 716, 621 and 585.+−.4 cm.⁻¹, as given in FIG.4.

In another aspect, a process for the preparation of polymorphic Form IIof crystalline minocycline base comprises dissolving and/or suspendingamorphous minocycline base in an organic solvent chosen from estersfollowed by crystallization from the mixture.

Preferably, the process comprises suspending amorphous minocycline basein an organic solvent chosen from esters, cooling the heterogeneousmixture to a temperature of from 0° C. to 30° C., the preferred rangebeing from 10° C. to 15° C. and isolating the Form II from the reactionmixture.

Any suitable ester may be used as solvent, but it is preferred to useethyl acetate.

In another aspect, polymorphic Form III of crystalline minocycline baseis provided. That this is a crystalline form of minocycline base, whichup until now has only been known in its amorphous form, is demonstratedby physical attributes whose application in this area is well known tothose skilled in the art.

Crystalline Form III of minocycline base has a characteristic X-raydiffraction pattern shown in FIG. 5 and an infrared spectrum of FIG. 6.

Crystalline Form III is characterised by an X-ray diffraction patternhaving peaks at 6.5, 10.0, 13.2, 15.1, 16.5, 17.9, 19.6, 20.2, 21.1,22.3, 23.7, 24.8, 26.4, 28.1 and 30.5.+−.0.2°2.theta., as given in FIG.5. It is further characterised by an infrared spectrum having peaks at1647, 1605, 1581, 1470, 1399, 1307, 1286, 1251, 1216, 1195, 1179, 1136,1094, 1058, 1024, 1000, 973, 950, 870, 825, 806, 716, 680, 634, 615,584, 515, 496 and 413.+−.4 cm⁻¹, as given in FIG. 6.

In another aspect, a process for the preparation of polymorphic Form IIIof crystalline minocycline base comprises dissolving and/or suspendingamorphous minocycline base in an organic solvent chosen from alcoholsfollowed by crystallization from the mixture.

Preferably, the process comprises suspending amorphous minocycline basein an organic solvent chosen from alcohols, cooling the heterogeneousmixture to a temperature of from 0° C. to 30° C., the preferred rangebeing from 10° C. to 15° C. and isolating the Form III from the reactionmixture.

Any suitable alcohol may be used a solvent, but it is preferred to useethanol.

The crystalline minocycline bases in Forms I, II and III obtained by theprocesses described above have a high purity with all the impuritiescontrolled, especially 4-epi minocycline, which is typically below 1.2%w/w (i.e., by weight of the base).

In another aspect, therefore, the invention provides crystallineminocycline base substantially free of 4-epi minocycline. Bysubstantially free, we mean that no more than about 1.2% impurity byweight of the polymorph (w/w) is present. Preferably the impurity levelis less than 1.2% w/w.

In a further aspect, therefore, the invention provides crystallineminocycline base comprising less than 1.2% w/w (by weight of the base)of 4-epi minocycline.

Another aspect of the invention provides processes for preparingamorphous minocycline base on an industrial scale, wherein theminocycline base is obtained in high purity, especially maintaining lowlevels of the content of 4-epi-minocycline.

In one aspect, there is provided a process for preparing amorphousminocycline base, which process comprises spray drying a solution orsuspension of minocycline, in an organic solvent, preferably chosen frommethyl tert-butyl ether, dichloromethane or isopropyl acetate

A preferred process for preparing amorphous minocycline base comprises:

1) dissolving minocycline base in one or more organic solvents to form asolution or a suspension

2) spray drying the solution or suspension obtained in step 1)

3) optionally drying the amorphous minocycline base so obtained, ifnecessary under vacuum, at a temperature of from 25° C. to 45° C.,preferably from 35° C. to 45° C.

Any suitable solvent may be used, and preferred solvents include methyltert-butyl ether, dichloromethane or isopropyl acetate.

Any suitable technique for the spray drying may be used. For example,conventional spray drying techniques (as will be clear to those skilledin the art) may be employed.

EXAMPLES

The following examples are provided to illustrate the present inventionand do not in any way limit its scope.

Example 1

Preparation of Form I of Crystalline Minocycline Base

Amorphous minocycline base (0.5 g) is suspended in methyl tert-butylether (4 ml) and the resulting heterogeneous mixture stirred for about 2hours at a temperature between 0° C. and 30° C., preferably between 10°C. and 15° C.

The product is filtered, washed with methyl tert-butyl ether (1 ml) anddried under vacuum at about 45° C.-50° C. to yield crystallineminocycline base.

Yield: 0.38 g

The XRPD pattern and infrared are presented in FIG. 1 and FIG. 2.

4-epi minocycline: 0.06% in area (HPLC)

Melting point 113° C.

Example 2

Preparation of Form I of Crystalline Minocycline Base

Amorphous minocycline base (0.5 g) is dissolved in methyl tert-butylether (6 ml) and the resulting solution stirred at a temperature between0° C. and 30° C., preferably between 10° C. and 15° C.

After about 5 minutes Form I of crystalline minocycline baseprecipitates from the solution.

The resulting suspension is filtered, washed with methyl tert-butylether (1 ml) and dried under vacuum at about 45° C.-50° C. to yield FormI of crystalline minocycline base.

Yield: 0.45 g.

Melting point: 113° C.

Example 3

Preparation of Form II of Crystalline Minocycline Base

Amorphous minocycline base (20 g) is suspended in ethyl acetate (160 ml)and the resulting heterogeneous mixture stirred for about 3 hours at atemperature between 0° C. and 30° C., preferably between 10° C. and 15°C.

The product is filtered, washed with ethyl acetate (10 ml) and driedunder vacuum at about 45° C.-50° C. to yield crystalline minocyclinebase.

Yield: 17.4 g

HPLC purity: 99.5% in area

4-epi minocycline: 0.11% in area.

Melting point: 187° C.

The XRPD pattern and infrared are presented in FIG. 3 and FIG. 4.

Example 4

Preparation of Form II of Crystalline Minocycline Base

Amorphous minocycline base (5 g) is dissolved in ethyl acetate (40 ml)and the resulting solution stirred for about 3 hours at a temperaturebetween 0° C. and 30° C., preferably between 10° C. and 15° C. whereuponForm II of crystalline minocycline base precipitated.

The product is filtered, washed with ethyl acetate (5 ml) and driedunder vacuum at about 45° C.-50° C. to yield Form II of crystallineminocycline base.

Yield: 3.2 g

Melting point: 187° C.

Example 5

Preparation of Form III of Minocycline Base

Amorphous minocycline base (0.5 g) is suspended in ethyl alcohol (2.5ml) and the resulting heterogeneous mixture stirred for at least 10hours at a temperature between 0° C. and

30° C. preferably between 10° C. and 15° C.

The product is filtered, washed with ethyl alcohol (0.5 ml) and driedunder vacuum at about 45° C.-50° C. to yield Form III of crystallineminocycline base.

Yield: 0.44 g

The XRPD pattern and infrared are presented in FIG. 5 and FIG. 6.

4-epi minocycline: 0.12% in area (HPLC)

Melting point: 193° C.

Example 6

Preparation of Amorphous Minocycline Base

A solution of minocycline base in dichloromethane, isopropyl acetate ormethyl tert-butyl ether was isolated by spray drying in conventionalspray drying equipment using an inlet temperature between 45° C. and105° C., and an outlet temperature between 30° C. and 75° C.

The isolated product can be used directly to obtain any of the Forms ofcrystalline minocycline base or can be subjected to a post drying stepunder vacuum at about 45° C. to yield pure amorphous minocycline base.

Yield: 24.5 g

HPLC purity: 98.6% in area

The XRPD pattern and Infra red are presented in FIG. 7 and FIG. 8.

1. A process for preparing amorphous minocycline base, which processcomprises spray drying a solution or suspension of minocycline in anorganic solvent.
 2. A process according to claim 2, wherein the solventis methyl tert-butyl ether, dichloromethane or isopropyl acetate.
 3. Aprocess according to claim 1, further including drying the amorphousminocycline base so obtained under vacuum.
 4. A process according toclaim 1, including drying at a temperature of from about 25° C. to about45° C.
 5. A process according to claim 1, including drying at atemperature of from about 35° C. to about 45° C.
 6. Crystallineminocycline base, Form I, made using the amorphous minocycline base ofclaim
 1. 7. Crystalline minocycline base, Form II, made using theamorphous minocycline base of claim
 1. 8. Crystalline minocycline base,Form III, made using the amorphous minocycline base of claim
 1. 9.Crystalline minocycline base substantially free of 4-epi minocyclinemade using the amorphous minocycline base of claim
 1. 10. Crystallineminocycline base substantially free of 4-epi minocycline made using theamorphous minocycline base of claim 1, wherein the content of 4-epiminocycline is below 1.2% w/w.
 11. Crystalline minocycline base havingForm I, II or III, made using the amorphous minocycline base of claim 1,comprising less than 1.2% w/w of 4-epi minocycline.
 12. Minocycline basecharacterized by being crystalline.
 13. Crystalline minocycline basesubstantially free of 4-epi minocycline.